Lec 04- Innate Immunity (Part 1) Flashcards
1
Q
What is the function of innate immunity?
A
- Initial host defense response to pathogens that prevents, controls, or eliminates infection
- Eliminates damaged cells and initiates tissue repair process
- Controls adaptive responses
2
Q
Innate immunity may keep the infection in check until _______.
A
more specialized adaptive immune responses are activated
3
Q
Steps of damaged cell elimination
A
1- RECOGNIZES and responds to host molecules that are stressed, damaged, and dead host cells
2- CLEARS cell debris by phagocytosis
3- STIMULATES and controls tissue remodeling
4
Q
How does innate immunity control adaptive responses to intracellular vs. extracellular pathogens?
A
- Provides danger signals»_space; alert adaptive immune system to respond
- Reacts in distinct ways to different microbes»_space; influences the type of adaptive immune response
5
Q
Innate Immunity component:
Cellular and chemical barriers
A
- skin
- mucosal epithelia
- antimicrobial molecules
6
Q
Innate immunity component:
Blood proteins
A
- complement
- acute phase proteins
- cytokines
- others
7
Q
Innate immunity component:
Cells
A
- phagocytes (macrophages/neutrophils)
- dendritic cells
- natural killer cells
- innate lymphoid cells
8
Q
3 Major Type of Defenses of Innate Immunity
A
-Inflammation
> Leukocytes and plasma proteins
-Physical barriers
> Skin and epithelial cells
-Anti-viral responses
> Inhibition of viral replication
9
Q
Specificity:
Innate vs. Adaptive
A
Innate:
- Pathogen-associated molecular patterns (PAMPs)
- Damage-associatd molecular patterns (DAMPs)
Adaptive:
-Fine structures of microbial and non microbial Ags
10
Q
Receptors:
Innate vs. Adaptive
A
Innate = Pattern recognition receptors (PRRs)
Adaptive = Greater diversity of BCRs and TCRs generated by somatic recombination
11
Q
Distribution of receptors:
Innate vs. Adaptive
A
Innate = NONCLONAL (identical receptors on various cells)
Adaptive = CLONAL (identical on a single cell, but different between 2 cells)
12
Q
Discrimination of self and non-self:
Innate vs. Adaptive
A
Innate = YES
Adaptive = YES
13
Q
Where are PRRs located?
A
- extracellularly
- endosomes
- cytosol
14
Q
What are the 5 families of microbial PRRS?
A
1- TLR family (surface and endosomal) 2- CLRs family 3- NOD-like receptors (NLRs) family 4- RIG-like receptors (RLRs) family 5- Cytosolic DNA sensors (CNS) family
15
Q
PRRs on the cell surface bind PAMPs from __________.
A
extracellular pathogens
16
Q
What do endosomal TLRs recognize?
A
nucleic acids of phagocytized microbes
17
Q
Which family of PRRs is an evolutionarily conserved family?
A
TLRs
18
Q
TLRs can form _______ or ________.
A
homodimers or heterodimers
19
Q
What do TLRs recognize?
A
Both PAMPs and DAMPs
20
Q
Which TLRs are expressed on the cell surface?
A
TLRs: 1 2 4 5 6
21
Q
Which TLRs are expressed in endosomes?
A
TLRs: 3 7 8 9
22
Q
Which TLRs use the adapter protein MyD88 and activate the transcription factors NF-kB and AP-1?
A
TLRs: 1 2 5 6
23
Q
Which TLR uses the adaptor protein TRIF and activates the IRF3 and IRF7 transcription factors?
A
TLR3
24
Q
Which TLR can activate both pathways?
A
TLR4
25
Which TLRs in the endosome use My D88 and activate both NF-kB and IRF7?
TLRs:
7
9
26
All TLRs signal through MyD88 except _______.
TLR3
27
Which TLRs also engage TIRAP?
TLR4 and the TLR2 subfamily (TLR 1,2,6)
28
Which TLR signals through TRIF?
TLR3
29
What is used in conjunction with TRAM in the TLR4-MyD88 independent pathway?
TRIF
30
TLRs are expressed on ______ cells
Immune cells
including macrophages and dendritic cells
31
Microbial lipoproteins activate mammalian immune cells through ________.
TLR2
32
LPS activates cells via ______.
TLR4
33
Through which TLR do bacterial DNA sequences containing unmethylated cytosine-guanosine dinucleotides (CpGs) work?
TLR9
34
TLR-dependent signaling pathways activate ______ which results in transcription of pro-inflammatory genes.
NF-kB
35
Which cytokine controls the adaptive T cell immune response?
IL-12
36
Activation of TLRs triggers ____.
antimicrobial pathways that directly kill the pathogen
37
What are the 2 ways activation of TLRs can be detrimental to the host?
- can contribute to tissue injury by inducing apoptosis
| - can lead to life-threatenting septic shock
38
Where is the secreted from of IL-1b and IL-18 produced?
in the inflammasome
39
From which family is the NLRP subfamily?
14 NOD-like receptors
40
How do NLRPs respond to cytosolic PAMPs and DAMPs?
- binding other proteins
| - forming signaling complexes (inflammasomes)
41
How do inflammasomes activate the enzyme caspase-1?
by recruitment to the complex
42
What is caspase-1?
a protease with cysteine residue in the active site
43
What is the main function of caspase-1?
to cleave the inactive cytoplasmic precursor forms of IL-1b and IL-18
44
What are the secreted forms of IL-1b and IL-18?
proinflammatory cytokines
45
What kind of complexes make up the scavenger receptor family?
Trimeric complexes of type II transmembrane polypeptides
46
What are the 3 extracellular structural domains of the scavenger receptor family?
1- SR cysteine-rich (SRCR) domain
2-The collagen-like domain, which is implicated in the binding of polyanionic ligands
3-The a-helical coiled-coil domain, believed to assist in receptor trimerization
47
What are the 3 domains on the Macrophage mannose receptor (MMR) and DEC-205?
1- cyesteine-rich N terminal domain
2- fibronectin-like domain
3- multiple calcium-dependent lectin domains that bind various carbohydrate ligands
48
What do scavenger receptors mediate?
the uptake of oxidized lipoproteins into cells
49
Which scavenger receptors are expressed on macrophages and mediate the recognition/phagocytosis of microorganisms?
SR-A and CD36
50
CD36 also functions as what?
- a coreceptor in TLR2/6 recognition
| - response to bacterially derived lipoteichoic acid and diacylated lipopeptides
51
SRs bind bacterial constituents based on _______ of bacterial LPS, lipoteichoic acid, nucleic acids, b-glucan, and proteins
negative charges
52
SRs KO mice have increased _________ with several microbial pathogens
increased susceptibility to infection
53
Receptors for carbohydrates belong to the _________ family.
C-type lectin family because they bind to carbohydrates
54
All receptors contain a conserved carbohydrate recognition domain for recognition of ______, ______, and ______.
- microbial mannose
- N-acetylglucosamine
- b-glucans
55
EUK carbohydrates are most often terminated by _______ and _______.
galactose and sialic acid
56
Where are soluble lectins found?
- blood
| - extracellular fluids
57
Where are integral membrane protein lectins found?
- surfaces of macrophages
- dendritic cells
- some tissue cells
58
Function of receptors for carbohydrates
- facilitate the phagocytosis of microbes
| - secretion of cytokines that promoted subsequent adaptive immune responses
59
What do mannose receptors recognize on microbial surfaces?
- terminal D-mannose
- L-fructose
- N-acetyl-D-glucosamine sugars
60
The mannose receptor is involved in __________ of microbes.
phagocytosis of microbes
61
3 types of epithelial barriers
- physical barrier to infection
- killing of microbes by locally produced antibiotics
- killing of microbes and infected cells by intraepithelial lymphocytes
62
What are defensins?
-small cationic antimicrobial peptides
63
What do defensins contain?
- cationic regions
| - hydrophobic regions
64
What produces defensins?
- epithelial cells of mucosal surfaces
| - granule-containing leukocytes (neutrophils, natural killer cells, CTLs)
65
What stimulates defensin synthesis?
- cytokines
| - microbial products
66
To what do defensins have direct toxicity?
Microbes
including:
- bacteria
- fungi
- enveloped viruses
67
Function of defensins
regulate activation of cells involved in inflammatory response to microbes
68
What produces cathelicidins?
-neutrophils
-barrier cells in the:
> skin
> GI tract
> respiratory tract
69
What are cathelicidins synthesized as?
| Cleaved into?
Synthesized as: an 18-kD 2-domain precursor protein
Cleaved into: 2 protective peptides
70
To what do cathelicidins have direct toxicity?
- Microorganisms
| - Activation of leukocytes
71
What is LL-37?
- The C-terminal fragment of cathelicidins
- Can bind and neutralize LPS
- Binds to DNA blocking AIM2 inflammasome activation
72
Functions of Anti-microbial Peptides (AMP)
- Wound repair
- Initiation of TLR9 activation
- Recruitment of T cells
- Mast cell de-granulation and histamine release >> vasodilation
- Recruitment of immature dendritic cells
- Promotion of angiogenesis
- Anti-endotoxin activity
- Killing microbes
73
Where do innate lymphoid cells (ILCs) develop?
from common bone marrow precursor
74
The common bone marrow precursor is identified by ______.
the Id2 transcription factor
75
What are the 3 subsets of Id2?
T-bet (ILC1)
GATA-3 (ILC2)
RORyt (ILC3)
76
How are the 3 subsets of Id2 distinguished?
by expression of distinct transcription factors and cytokines produced
77
Which cytokines does ILC1 produce?
IL-2
IL-18
Defense against viruses
78
Which cytokines does ILC2 produce?
IL-25
IL-33
Allergic inflammation
79
Which cytokines does ILC3 produce?
IL-1
IL-23
Intestinal barrier function
Lymphoid organogenesis
80
Functions of natural killer cells
- RECOGNIZE ligands on infected cells or stressed cells
- KILL infected or stressed host cells
- ELIMINATE reservoirs of infection
- RELEASE intracellular pathogens for phagocytosis
81
What do natural killer cells respond to and secrete?
Respond to: IL-12 produced by macrophages
Secrete: IFN-y
82
Function of IFN-y
activates macrophages to kill phagocytized microbes
83
What are Killer cell immunoglobulin (Ig) like receptors (KIRs)?
NK-cell activating receptors
84
Function of Killer cell immunoglobulin (Ig) like receptors (KIRs)?
- recognize ligands on target cells
| - activate protein tyrosine kinases (PTKs)
85
What inhibits activation signal of natural killer cells?
The inhibitory receptors that:
- Recognize class I MHC molecules
- Activate protein tyrosine phosphatases (PTPs)
86
Do NK cells kill class I MHC-expressing healthy cells?
NO!
87
MHC
major histocompatability complex
88
Any inhibition of class I MHC expression on infected cells leads to what?
- NK cell inhibitory receptor not engaged
| - The activating receptor functions unopposed to trigger activation of NK cells
89
KARs
Killer Activation Receptors
90
NCR
Natural Cytotoxicity Receptors
-(with stimulation) mediate NK killing and release of IFN-y
